trial [3]. Further, the editorial makes an effective argument toinclude, “high risk early ovarian cancer patients in phase IIIrandomized trials in advanced ovarian cancer,” which currentlyroutinely employ 6 cycles of platinum-based chemotherapy.

Considering this reasonable recommendation for how high riskearly stage ovarian cancer patients should be managed in theclinical trials setting, the, “24% non-statistically significant,”reduction in the risk of recurrence associated with 6 cycles ofcarboplatin/paclitaxel in this seriously underpowered study andthe recognized limited impact of “second-line” therapy in ovariancancer following documented disease progression, the statedconclusions for this studymust be vigorously challenged. It is alsoimportant to note that carboplatin was employed at an AUC levelof 7.5 in this trial, a higher concentration than is currently utilizedby the GOG in its advanced ovarian cancer chemotherapy studies(AUC 6), which raises additional concerns for the relevance of thereport's conclusion that 6 cycles of this program are associatedwith “more toxicity”.

In summary, this study should not be used to justify under-treatment of patients with early stage high risk ovarian cancer, aclinical condition for which chemotherapy is being adminis-tered with legitimate curative intent.

References

[1] Bell J, Brady MF, Young RC, et al. Randomized phase III trial of threeversus six cycles of adjuvant carboplatin and paclitaxel in early stageepithelial ovarian carcinoma: a Gynecologic Oncology Group study.Gynecol Oncol 2006;102:432–9.

[2] Vergote I, Amant F. Time to include high-risk early ovarian cancer inrandomized phase III trials of advanced ovarian cancer. Gynecol Oncol2006;102:415–7.

[3] Markman M. Informing patients with cancer of “new findings” that mayinfluence their willingness to participate in research studies. Cancer2003;98:885–7.

Maurie MarkmanDepartment of Gynecologic Medical Oncology,

University of Texas M.D. Anderson Cancer Center,1515 Holcombe Boulevard, Houston, TX 77030, USA

E-mail address: mmarkman@mdanderson.org.

24 October 2006

doi:10.1016/j.ygyno.2007.01.006

Response to Dr. Markman's letter bRe: dRandomized phaseIII trial of three versus six cycles of carboplatin andpaclitaxel in early stage epithelial ovarian carcinoma: AGynecologic Oncology Group StudyTQ

To the Editor:

The authors appreciate Dr. Markman's continuing interestand commentary on the Gynecologic Oncology Group's (GOG)trial comparing 3 versus 6 cycles of carboplatin and paclitaxelfor high-risk early-stage epithelial ovarian carcinoma [1].

Dr. Markman believes that the, “stated conclusions for thisstudy must be vigorously challenged”. He concurs with anaccompanying editorial suggesting that these high-risk early-stage patients be included in future advanced-stage trials [2]. Heconcludes that, “this study should not be used to justify under-treatment…” of this group of patients.

The authors of this GOG trial do not clearly understand themeaning of Dr. Markman's “vigorous challenge” of the study'sconclusion and have previously responded in more detail to Dr.Markman's comments on this trial [3]. The conclusion from thisstudy was simply a statement of the facts without bias or authorprejudice. Specifically, 6 cycles is associated with an estimated5% reduction in the absolute probability of cancer recurringwithin 5 years. Not only was this reduction not statisticallysignificant, 6 cycles was more toxic than 3 cycles. Clearly, apatient who has not experienced any significant ill-effectsduring the first 3 cycles of treatment may opt for this possible,relatively small, margin of benefit from 3 additional cycles,while one who struggles with treatment may justifiably preferno additional therapy.

The authors would like to direct the readers to that part of thediscussion that reviews the history of treatments for high-riskearly ovarian epithelial cancers. Interestingly, numerous priorregimens, platinum and non-platinum, for treating this group ofpatients have resulted in very similar recurrence rates (15–30%).Dr. Markman apparently feels that 6 cycles of chemotherapyshould be the treatment of choice for this group of patients,which includes stages I and II. The GOG has decided for thefuture to shift stage II patients to advanced-stage protocols,which typically prescribe 6–8 cycles of a platinum–taxaneregimen. For early-stage disease, the current GOG trial showsthat 6 cycles is unlikely to reduce the recurrence rate by 50%compared to 3 cycles—the risk reduction that was considered tobe clinically significant when the trial was initiated. Further-more, both treatment armsmay not be any better thanmany otherhistorical regimens. An important unanswered question iswhether a select group of stage I patients who have undergonethorough surgical staging benefit from any adjuvant treatment.The recent ACTION trial by our European colleagues lendscredence to this suggestion because in that trial, optimally stagedpatients who were observed had both disease-free and overallsurvival rates similar to patients who received adjuvantchemotherapy (83% vs. 80% and 87% vs. 89%) [4]. Thus,incorporating patients diagnosed with early-stage disease,especially stage I disease, into trials with advanced-stage diseasedismisses the significance of this question and unjustifiablyaccepts the adage that more must be better. Future prospectivetrials should investigate biological, cellular, and molecularmarkers that might identify which cancers recur seeminglydespite adjuvant treatment in optimally staged patients.

References

[1] Markman M. Re: “Randomized phase III trial of three versus six cycles ofcarboplatin and paclitaxel in early stage epithelial ovarian carcinoma: AGynecologic Oncology Group Study”. Gynecol Oncol 2007;105:279–80(this issue).

280 Letters to the Editor

[2] Vergote I, Amant F. Time to include high risk early ovarian cancer inrandomized phase III trials of advanced ovarian cancer. Gynecol Oncol2006;102:415–7.

[3] Bell JG, Brady M, Copeland L. The ethics of reporting and disseminatingresults of clinical research trials. Cancer 2004;100:1107–9.

[4] Trimbos JB, Vergote I, Bolis G, et al. Impact of adjuvant chemotherapy andsurgical staging in early-stage ovarian carcinoma: European Organisationfor Research and Treatment of Cancer – Adjuvant ChemoTherapy inOvarian Neoplasm trial. J Natl Cancer Inst 2003;95:113–25.

Jeffrey BellCancer Services, Riverside Methodist Hospital,

Columbus, OH, USAE-mail address: bellj2@yahoo.com.

24 November 2006

doi:10.1016/j.ygyno.2007.01.007

281Letters to the Editor